title: Potent inhibition of the C-P lyase nucleosidase PhnI by Immucillin-A triphosphate.
abstract: The C-P lyase complex in bacteria catalyzes the transformation of phosphonates to orthophosphate under conditions of phosphate starvation. The first committed step in the C-P lyase-catalyzed reaction is the displacement of adenine from MgATP by phosphonate substrates, yielding ribose-1-phosphonate-5-triphosphate. In the C-P lyase complex, this reaction is catalyzed by the nucleosidase PhnI and modulated by the addition of PhnG, PhnH, and PhnL. Here we describe the synthesis of Immucillin-A triphosphate, a mimic of the transition state structure for the nucleosidase reaction catalyzed by PhnI. This compound inhibits PhnI with a dissociation constant of 20 nM at pH 7.5.
authors.affiliation: Department of Chemistry, Texas A&M University , College Station, Texas 77840, United States.
authors.forename: Siddhesh S
authors.initials: SS
authors.lastname: Kamat
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Burgos
authors.forename: Frank M
authors.initials: FM
authors.lastname: Raushel
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives; D000255:Adenosine Triphosphate / Q000378:metabolism; D002384:Catalysis; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008956:Models, Chemical; D063065:Organophosphonates / Q000378:metabolism; D010428:Pentosephosphates / Q000378:metabolism; D011122:Polyphosphates / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*
chemical_list: D029968:Escherichia coli Proteins; D063065:Organophosphonates; D010428:Pentosephosphates; D011122:Polyphosphates; D011759:Pyrrolidines; C025202:ribose-5-triphosphate; D000255:Adenosine Triphosphate; D008190:Lyases; C051328:carbon-phosphorus lyase; D008274:Magnesium; D000225:Adenine; D000241:Adenosine; C005692:triphosphoric acid; C517546:galidesivir